Abstract 9-THC is the major psychoactive cannabinoid in marijuana. Advanced understanding of its pharmacology and the major cannabinoid receptor subtypes (CB1 and CB2) as well as their localization (CB2predominantly on B lymphocytes and natural killer cells) has resulted in identification of multisystemic biomedical effects. Particularly important is the potential of 9-THC modulation of immune function in human immunodeficiency virus (HIV) infected individuals. Our studies indicate that chronic 9-THC treatment attenuates viral load and tissue inflammation in simian immunodeficiency virus (SIV) infected non-human primates, significantly decreasing morbidity and mortality from SIV infection. In addition, 9-THC decreased viral replication in an in vitro assay. While the ability of cannabinoids to suppress inflammation and viral replication has been reported by others and confirmed by our ongoing studies, the mechanisms involved are not known. Preliminary data obtained in preparation for this application revealed increased expression of a distinct miRNA profile associated with decreased immune activation and anti-inflammatory properties (based on predicted targets) in CD4+ T lymphocytes, intestinal mucosa, and brain of THC-treated SIV-infected animals. These findings clearly suggest that the overall mechanisms mediating the protective effects of cannabinoids involve novel epigenomic regulatory factors/mechanisms in need of systematic investigation. The overall hypothesis of this proposal is that chronic 9-THC treatment decreases pro-inflammatory gene expression and viral replication through epigenomic (non-coding RNAs and DNA methylation) mechanisms. As a result, chronic cannabinoid treatment delays disease progression in SIV-infected non-human primates. This hypothesis will be tested with the following specific aims: 1. Demonstrate that chronic cannabinoid treatment decreases tissue inflammation in SIV-infected rhesus macaques. 2. Identify the epigenomic (including miRNAs and DNA methylation) mechanisms of cannabinoid-induced suppression of inflammation in SIV-infected rhesus macaques. 3. Examine the direct and indirect epigenomic mechanisms by which cannabinoids decrease viral replication. The proposed studies will explore the epigenomic (miRNA and DNA methylation) mechanisms involved in the anti-inflammatory effects and suppression of viral replication associated with prolonged survival in chronic THC-treated SIV-infected animals.